A disintegrin-like metalloprotease domain with thrombospondin type I motifs (ADAMTS)-like, ADAMTSL, is a subgroup of the ADAMTS superfamily that shares particular protein domains with the ADAMTS protease, including thrombospondin type I repeats, a cysteine-rich domain, and an ADAMTS spacer, but lacks the catalytic and disintegrin-like domains [40]. A recent study has demonstrated that ADAMTSL2 mutations cause geleophysic dysplasia, an autosomal recessive disorder similar to MFS, through the dysregulation of TGF-β signaling [41]. A homozygous mutation in ADAMTSL4 also causes autosomal-recessive isolated ectopia lentis, another disease similar to MFS which is characterized by the subluxation of the lens as a result of disruption of the zonular fibers [42]. The novel ADAMTSL family molecules ADAMTSL6α and 6β were recently identified by in silico screening for novel ECM proteins produced from a mouse full-length cDNA database (FANTOM). These proteins are localized in connective tissues, including the skin, aorta and perichondrocytes. Among ADAMTSL6, ADAMTSL6β has shown to associated with fibrillin-1 microfibrils through its direct interaction with the N-terminal region of fibrillin-1 and promotes fibrillin-1 matrix assembly in vitro and in vivo [43]. These findings suggest a potential clinical application of ADAMTSL6β as a novel MFS therapy by promoting fibrillin-1 microfibril assembly and regulating TGF-β activation.

It is also suggested that the administration of fibrillin-1 microfibrils provides a novel therapeutic strategy for the treatment of periodontal disease.

To investigate whether ADAMTSL6β plays a critical role in microfibril assembly in connective tissues, we generated ADAMTSL6β transgenic mice (TSL6β-TG mice) in which the transgene is expressed in the whole body. Since ADAMTSL6β has shown to be expressed in the aorta and skin, we investigated microfibril assembly of these tissues in the TSL6β-TG mice. Immunohistochemical analysis revealed that ADAMTSL6β positive microfibril assembly was barely detectable in WT mice but strongly induced in the aorta of TSL6β-TG mice (Fig. 14.2). Histological analysis revealed that microfibrils are clearly increased in the aorta and that microfibril assembly is also induced in the skin and PDL of TSL6β − TG mice. This confirmed that ADAMTSL6β induces fibrillin-1 microfibril assembly in connective tissue such as the aorta, skin and PDL.

To investigate whether ADAMSL6β contributes to PDL formation, we first examined its expression patterns during PDL forming stage of DF in the developing tooth germ. In situ hybridization analysis revealed that ADAMSL6β was strongly expressed in the PDL forming stage of the DF however ADAMSL6β expression was significantly downregulated in the adult PDL. Immunohistochemical analysis further revealed that ADAMSL6β is detectable in assembled microfibril-like structures during the PDL forming stage of the DF, and in organized microfibrils in the adult PDL. Because developmental processes involve similar mechanisms to wound healing, we next determined whether ADAMSL6β is involved in PDL microfibril assembly during wound healing using a tooth replantation model. Histochemical analysis revealed that both fibrillin-1 and ADAMSL6β expressions were found to be clearly induced during wound healing of PDL, but to decrease again after healing. These findings suggested that ADAMSL6β was involved in microfibril formation during PDL formation/regeneration.

Since oxytalan fiber, a principal elastic fiber system of PDL is composed of fibrillin-1 microfibrils and does not contain significant amounts of elastin [44, 45], this composition suggests that PDL will have an increased susceptibility to breakdown in MFS compared with other elastic tissues composed of both elastin and fibrillin-1 [46]. We demonstrated that ADAMSL6β is highly expressed in DF during PDL forming stage. In addition, intense expression of ADAMTSL6β can be seen in wound healing process of PDL, indicating that this protein involved in recovery of damaged PDL. Using an animal model of MFS, we demonstrate that local administration of ADAMSL6β can rescue fibrillin-1 microfibril formation through the promotion of fibrillin-1 microfibril assembly in PDL (Fig. 14.3). These results strongly indicate that ADAMTSL6β is essential for fibrillin-1 microfibril formation and suggest a novel therapeutic approach to the treatment of periodontal disease with MFS.